Henry P. Ciolino
National Institutes of Health
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Featured researches published by Henry P. Ciolino.
Biochemical Pharmacology | 1998
Henry P. Ciolino; Phillip J. Daschner; Thomas T.Y. Wang; Grace Chao Yeh
We examined the interaction of curcumin, a dietary constituent and chemopreventive compound, with the carcinogen activation pathway mediated by the aryl hydrocarbon receptor (AhR) in MCF-7 mammary epithelial carcinoma cells. Curcumin caused a rapid accumulation of cytochrome P450 1A1 (CYP1A1) mRNA in a time- and concentration-dependent manner, and CYP1A1 monooxygenase activity increased as measured by ethoxyresorufin-O-deethylation. Curcumin activated the DNA-binding capacity of the AhR for the xenobiotic responsive element of CYP1A1 as measured by the electrophoretic-mobility shift assay (EMSA). Curcumin was able to compete with the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin for binding to the AhR in isolated MCF-7 cytosol, indicating that it interacts directly with the receptor. Although curcumin could activate the AhR on its own, it partially inhibited the activation of AhR, as measured by EMSA, and partially decreased the accumulation of CYP1A1 mRNA caused by the mammary carcinogen dimethylbenzanthracene (DMBA). Curcumin competitively inhibited CYP1A1 activity in DMBA-treated cells and in microsomes isolated from DMBA-treated cells. Curcumin also inhibited the metabolic activation of DMBA, as measured by the formation of DMBA-DNA adducts, and decreased DMBA-induced cytotoxicity. These results suggest that the chemopreventive effect of curcumin may be due, in part, to its ability to compete with aryl hydrocarbons for both the AhR and CYP1A1. Curcumin may thus be a natural ligand and substrate of the AhR pathway.
Breast Cancer Research and Treatment | 1999
Phillip J. Daschner; Henry P. Ciolino; Cathie A. Plouzek; Grace Chao Yeh
The expression, DNA binding, and transactivating activity of activator protein 1 (AP-1) was examined in a series of multidrug resistant (MDR) MCF-7 human breast cancer cells that have increasing levels of MDR1 gene expression. We observed an increase in the amount of both c-jun and c-fos mRNA in cells with 12-, 65-, or 200-fold higher resistance to adriamycin when compared to drug-sensitive MCF-7 wild type (WT) cells. Electrophoretic mobility shift assays (EMSA) demonstrated an increase in the DNA binding activity of an AP-1 complex in nuclear extracts from MDR MCF-7 cells when compared to extracts from WT cells. We observed a proportional increase in luciferase expression from a reporter vector containing consensus AP-1 binding sites in transiently transfected MDR cells when compared to WT cells, indicating that AP-1 mediated gene expression is increased in drug-resistant MCF-7 cells. Since the MDR1 promoter contains a putative AP-1 binding site, we used EMSA to examine AP-1 binding activity to an oligonucleotide probe that contained the relevant MDR1 promoter sequences (−123 to −108). Nuclear extracts from resistant MCF-7 cells displayed an increased level of DNA binding of Jun/Jun dimers to the probe, indicating that AP-1 was capable of binding to this promoter site. A luciferase reporter construct containing triplicate copies of the MDR1 promoter sequence was expressed at higher levels in transiently transfected MDR cells when compared to expression in WT cells. Co-transfection of WT cells with a c-jun expression vector and either of the AP-1 luciferase constructs demonstrated that c-jun could activate gene expression from both the consensus and the MDR1 AP-1 sites in a dose dependent manner. In addition, RT-PCR and western blot analysis showed that levels of MDR1 mRNA and Pgp were increased in c-jun transfected WT cells. Taken together, these data indicate that increased AP-1 activity may be an important mediator of MDR by regulating the expression of MDR1.
Free Radical Biology and Medicine | 1997
Henry P. Ciolino; Rodney L. Levine
Exposure of bovine aortic endothelial cells in vitro to oxidative stress causes a cascade of changes in cell function, culminating in cell death if the stress is sufficiently severe. Oxidative modification of proteins, as measured by the reaction of 2,4-dinitrophenylhydrazine with carbonyl groups of oxidized proteins, increased three- to fourfold in endothelial cells exposed to hydrogen peroxide or to a xanthine/xanthine oxidase system. The increase in oxidative modification of protein occurred rapidly, preceding loss of cellular ATP and eventual cell death. Oxidative modification of protein was paralleled by loss of activity of the key metabolic enzymes, glucose-6-phosphate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase. The finding that oxidative modification of protein is an early event following oxidative stress suggests that oxidative modification of protein is not only a marker for oxidative damage but also a causal factor in oxidative injury.
European Journal of Cancer | 1999
Henry P. Ciolino; Robert Clarke; Grace Chao Yeh; C.A Plouzek
The transmembrane transport pump P-glycoprotein (Pgp) causes the efflux of chemotherapeutic agents from cells and is believed to be an important mechanism in multidrug resistance (MDR) in mammary tumours. In the present study we demonstrate that an extract of the common dietary herb rosemary (Rosemarinus officinalis Labiatae), increases the intracellular accumulation of commonly used chemotherapeutic agents, including doxorubicin (DOX) and vinblastine (VIN), in drug-resistant MCF-7 human breast cancer cells which express Pgp. Rosemary extract (RE) inhibits the efflux of DOX and VIN, which are known to be substrates of Pgp, but does not affect accumulation or efflux of DOX in wild type MCF-7 cells, which lack Pgp. Treatment of drug-resistant cells with RE increases their sensitivity to DOX, which is consistent with an increased intracellular accumulation of the drug. RE blocks the binding of the VIN analogue azidopine to Pgp. Thus, it appears that RE directly inhibits Pgp activity by inhibiting the binding of drugs to Pgp.
Cancer Research | 2004
Christopher J. MacDonald; Henry P. Ciolino; Grace Chao Yeh
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant, that has been linked with a variety of deleterious effects on human health, including increased cancer rates and reproductive anomalies. The detrimental effects of TCDD are mediated via the aryl hydrocarbon receptor (AhR), a transcription factor that regulates the expression of the carcinogen-activating enzymes cytochromes P-450 (CYP) 1A1, 1A2, and 1B1. In the present study, we examined the ability of synthetic derivatives of salicylic acid to affect TCDD-stimulated AhR-mediated signal transduction in human hepatoma HepG2 cells. Salicylamide (SAL), an analgesic drug, caused a potent and long-lasting inhibition of TCDD-induced CYP enzyme activity. Acetylsalicylic acid (aspirin) and the naturally occurring phytochemical salicylic acid had no effect on CYP activity. SAL inhibited the increase in CYP1A1, -1A2, and -1B1 mRNA levels that occurs on exposure to TCDD. TCDD-induced transcription of these genes was also inhibited by SAL, but not by aspirin or salicylic acid, as demonstrated by luciferase reporter assays. The transcription of the CYP1 family of genes is regulated by the interaction of TCDD-activated AhR with the xenobiotic-responsive element present in the promoter regions of these genes. As shown by electrophoretic mobility shift assay, SAL completely blocked the binding of TCDD-activated AhR to the xenobiotic responsive element. Also, SAL substantially blocked the binding of TCDD to the cytosolic AhR. These results demonstrate that SAL, a commonly used analgesic, is a potent inhibitor of AhR-mediated signal transduction, and may be an effective agent in the prevention of TCDD-associated disease.
Advances in Experimental Medicine and Biology | 2001
Henry P. Ciolino; Grace Chao Yeh
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor of the basic helix-loop-helix family) It binds and is activated by a number of compounds, including polycyclic aromatic hydrocarbons (PAH) such as benzo[a]pyrene (B[a]P), which are generated during the combustion of fossil fuels and are present in tobacco smoke and smoked meats. The AHR also binds halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), which is a contaminant formed during the manufacture of chlorophenols (for chemical structures see Fig. 1). Both these classes of AHR ligands are persistent environmental pollutants and cause a variety of toxic and carcinogenic effects that are mediated by the AHR.
International Journal of Cancer | 2007
Henry P. Ciolino; Sara Bass; Christopher J. MacDonald; Robert Y.S. Cheng; Grace Chao Yeh
Sulindac is a nonsteroidal antiinflammatory drug that has been demonstrated to be a potent chemopreventive agent against colorectal cancer in both human and animal models. In vivo, sulindac may be reversibly reduced to the active antiinflammatory compound, sulindac sulfide, or irreversibly oxidized to sulindac sulfone. Sulindac has also been shown to inhibit polycyclic aromatic hydrocarbon (PAH)‐induced cancer, but the molecular mechanisms of its antitumor effect remain unclear. In this study, we investigated the effects of sulindac and its metabolites on the expression of enzymes that metabolize and detoxify PAHs in 2 human colon cancer cell lines, LS180 and Caco‐2. Sulindac and sulindac sulfide induced a sustained, concentration‐dependent increase in CYP enzyme activity as well as an increase in the mRNA levels of CYP1A1, CYP1A2 and CYP1B1. Sulindac and sulindac sulfide induced the transcription of the CYP1A1 gene, as measured by the level of heterogeneous nuclear CYP1A1 RNA and verified by the use of actinomycin D as a transcription inhibitor. Chromatin immunoprecipitation assays demonstrated that sulindac and sulindac sulfide also increased the nuclear level of activated aryl hydrocarbon receptor, the transcription factor which mediates CYP expression. Additionally, sulindac and both metabolites increased the activity and mRNA expression of the carcinogen detoxification enzyme NAD(P)H:quinone oxidoreductase, as well as the expression of UDP‐glucuronosyltransferase mRNA. These results show an overall upregulation of carcinogen metabolizing enzymes in colon cancer cells treated with sulindac, sulindac sulfide and sulindac sulfone that may contribute to the established chemoprotective effects of these compounds.
Journal of Nutritional Biochemistry | 2011
Henry P. Ciolino; Zhaoli Dai; Vidhya Nair
Aromatase converts androgens into estrogens and is thought to supply a local source of estrogen that facilitates the growth of hormone-responsive tumor cells. Inhibition of aromatase is therefore an important chemopreventive strategy. We investigated the effect of retinol and selected retinoids on the activity and expression of aromatase in two human carcinoma cell lines in vitro. Retinol (ROH) and all-trans retinoic acid (ATRA) significantly inhibited aromatase activity in a concentration-dependent manner in microsomes isolated from JEG-3 human placental carcinoma cells, whereas 9-cis and 13-cis retinoic acid had significant inhibitory activity only at the highest concentrations tested. Similar results were observed in an assay of cellular aromatase activity in MCF-7 human breast cancer cells. Enzyme kinetic studies by double-reciprocal plot demonstrated that ROH inhibited microsomal aromatase activity in a mixed manner. In addition, ROH suppressed both the basal and cAMP-induced expression of aromatase mRNA in MCF-7 cells and inhibited transcription controlled by a cAMP-responsive element. These results suggest that aromatase activity and expression are a molecular target of ROH and chemopreventive retinoids, an activity that may underlie, in part, their inhibitory effects on hormone-dependent cancer.
International Journal of Cancer | 2003
Henry P. Ciolino; Chistopher MacDonald; Omar Memon; Maame Dankwah; Grace Chao Yeh
We investigated the effect of the steroid hormone dehydroepiandrosterone (DHEA) on the hepatic expression and activity of carcinogen‐activating enzymes, the cytochromes P450 (CYP) 1A1, 1A2 and 1B1, in Sprague‐Dawley rats. In animals fed DHEA at 200 or 400 mg/kg body weight every other day for 2 weeks prior to exposure to the aryl hydrocarbon dimethylbenz[a]anthracene (DMBA, 5 mg/kg), there was a dose‐dependent decrease in hepatic CYP activity, as measured by ethoxyresorufin‐O (EROD) assay, from 37.1 to 22.9 and 14.7 pmoles/min/10 μg microsomes, respectively. DHEA did not directly inhibit microsomal EROD activity, however, leading us to investigate its effects on enzyme expression. To test this, we examined protein and mRNA levels of the enzymes. Western blot for CYP1A1 and CYP1A2 showed that DHEA inhibited the increase in hepatic CYP1A1 and CYP1A2 enzyme levels that are normally induced by DMBA. DMBA‐induced increase in expression of CYP1A1, CYP1A2 and CYP1B1 mRNA was similarly blunted in DHEA‐treated animals. DHEA was also able to significantly reduce the basal expression of CYP1A1 and CYP1A2 but not of CYP1B1. These results indicate that DHEA regulates the expression and, hence, the activity of hepatic carcinogen‐activating enzymes in vivo, and this may be an important mechanism of its chemopreventive activity. Published 2003 Wiley‐Liss, Inc.
Cancer Research | 2011
Maruf Khan; Linda A. deGraffenried; Bob G. Sanders; Henry P. Ciolino
Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Renal Cell Carcinoma (RCC) has low 5 year survival rate and is resistant to radiation and chemotherapy. Phenethyl Isothiocyanate (PEITC) is a naturally occurring phytochemical that has a variety of anti-cancer properties. Here we explore two anti-cancer properties of PEITC: induction of apoptosis and induction of cell cycle arrest in RCC cell lines and the underlying mechanisms. Methods: We used two human RCC cell lines Caki-1 and Caki-2. Survival and cell proliferation was assayed using Calcein AM. Annexin V staining was used to measure apoptosis. Caspase-3/7 induction was measured using a fluorescent substrate. Cell Cycle was studied using Propidium Iodide staining. DNA damage was determined using H2AX-γ antibody. Protein expression and phosphorylation was determined using immunoblotting. Results: PEITC significantly reduced survival of Caki-1 and Caki-2 cells and inhibited their proliferation as determined by Calcein AM. 15 and 20 μM PEITC induced apoptosis (revealed by Annexin V staining) in both cell lines and induced caspase-3/7 activity. Western blot analysis revealed caspase-8, caspase-9 and Bid cleavage suggesting that the apoptosis is mediated through the extrinsic pathway. Lower doses (up to 10 μM) arrested Caki-1 cells in G2/M phase, and this was associated with an increase p38 and MK2 (Thr334) phosphorylation (as revealed by Western Blot). The p38 inhibitor SB203850 inhibited this G2 arrest induced by PEITC. In order to determine if DNA damage was responsible for the apoptosis and G2 arrest, we used an antibody to H2AX-γ phosphorylation. 15 and 20 µM treatment resulted in increased H2AX-γ phosphorylation, but this was completely blocked by caspase-3 inhibitor. Conclusion: PEITC induces apoptosis in Caki-1 and Caki-2 cells by a mechanism that likely involves the extrinsic pathway. We will use immunoblotting and siRNA to determine which of the extrinsic receptors (DR4, DR5, TRAIL or FAS) is responsible for this apoptosis induction. PEITC does not cause direct DNA damage to the cells; the observed DNA damage is a result of the apoptotic process and is blocked by caspase-3 inhibitors. PEITC induces G2/M arrest in Caki-1 cells and the mechanism is dependent on p38 phosphorylation which activates MK2. Inducing cell cycle arrest and apoptosis may play an important role in the anti-cancer properties of PEITC. Fully understanding the mechanism by which PEITC induces apoptosis and cell cycle arrest in RCC cells may lead to development of novel chemotherapeutic drugs against RCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4222. doi:10.1158/1538-7445.AM2011-4222